4
Discovery Research for Rare Diseases and Orphan Product Development

I could see there was a transformation of cancer treatment on thehorizon thanks to breakthroughs in biochemistry and genomics.I wanted to be part of that, which is why I was a physician-researcher… . By the late 1980s, C.M.L. [chronic myeloid leuke-mia], though rare, was a cancer that scientists knew a lot about.We knew, for instance that a chromosomal abnormality existed inevery C.M.L. patient. We knew that this abnormality created anenzyme that caused the uncontrolled growth of cancer cells… . Ifyou want to develop targeted chemotherapies, C.M.L. is the diseaseto study. We know the most about it—and, if we can figure out away to block this enzyme, we can turn off the cancer switch.

Interview with Brian Druker (Dreifus, 2009)

The research undertaken by Brian Druker and his colleagues and predecessors offers a classic example of the foundation that basic research builds for the subsequent development of therapies for rare diseases. Breakthroughs in biochemistry and genomics, as well as advances in computational tools, have transformed the process of research and drug development. The process begins with basic laboratory studies that reveal the molecular mechanisms of disease, which related to a chromosomal abnormality in the case of chronic myelogenous leukemia (CML). This foundation leads to the discovery of biomarkers for rare conditions and the discovery of potential biological targets on which drugs can act. The target in CML is a rogue enzyme created by the mutated chromosomes, which triggers uncontrolled cell growth. Once a target is defined, the process shifts from basic research

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4
Discovery Research for Rare Diseases
and Orphan Product Development
I could see there was a transformation of cancer treatment on the
horizon thanks to breakthroughs in biochemistry and genomics.
I wanted to be part of that, which is why I was a physician-
researcher. . . . By the late 0s, C.M.L. [chronic myeloid leuke-
mia], though rare, was a cancer that scientists knew a lot about.
We knew, for instance that a chromosomal abnormality existed in
every C.M.L. patient. We knew that this abnormality created an
enzyme that caused the uncontrolled growth of cancer cells. . . . If
you want to develop targeted chemotherapies, C.M.L. is the disease
to study. We know the most about it—and, if we can figure out a
way to block this enzyme, we can turn off the cancer switch.
Interview with Brian Druker (Dreifus, 2009)
The research undertaken by Brian Druker and his colleagues and prede-
cessors offers a classic example of the foundation that basic research builds
for the subsequent development of therapies for rare diseases. Breakthroughs
in biochemistry and genomics, as well as advances in computational tools,
have transformed the process of research and drug development. The pro-
cess begins with basic laboratory studies that reveal the molecular mecha-
nisms of disease, which related to a chromosomal abnormality in the case
of chronic myelogenous leukemia (CML). This foundation leads to the
discovery of biomarkers for rare conditions and the discovery of potential
biological targets on which drugs can act. The target in CML is a rogue
enzyme created by the mutated chromosomes, which triggers uncontrolled
cell growth. Once a target is defined, the process shifts from basic research

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RARE DISEASES AND ORPHAN PRODUCTS
to the discovery of a therapeutic approach. Imatinib mesylate (Gleevec),
the drug discovered by Druker, specifically deactivates the enzyme target
in CML. It was approved by the Food and Drug Administration (FDA) in
2001 and is now used not only for CML but also for other rare cancers.
Increased knowledge of kinase inhibitors (of which imatinib was the first)
is supporting the development of more potent, second-generation drugs for
CML that may also be less susceptible to resistance (Sawyers, 2010).
Today, as a result of scientific and technological innovations, much
of the basic research initially undertaken with CML could be done more
quickly, inexpensively, and easily. For example, identification of the genetic
cause of conditions that are clearly inherited used to involve speculative
approaches and laborious analytical tools. The sequencing of the human
genome has spawned an array of rapid and relatively inexpensive DNA
analysis tools that have the potential to foster more targeted and efficient
therapeutics development for rare diseases. Advances in the scientific un-
derstanding of disease mechanisms likewise are helping researchers focus
more efficiently and effectively on potential therapeutic targets. As a result,
the future holds the promise of continued innovation that will further ac-
celerate biomedical research to the benefit of patients with rare as well as
common diseases.
As discussed in Chapter 1, research on rare diseases can illuminate dis-
ease mechanisms and therapeutic opportunities for more common diseases.
Box 4-1 briefly summarizes several additional examples of rare diseases
research that have yielded broader knowledge.
Many of the same approaches and techniques are used to study both
rare and common diseases, but research on rare diseases faces some spe-
cial barriers and constraints. One is the sheer number of rare diseases,
an estimated 5,000 to 8,000. Many of the challenges stem from the low
prevalence that is the defining characteristic of rare diseases. Particularly
for extremely rare conditions, the small numbers of affected individuals
means a dearth of biological specimens, which severely limits studies of
disease mechanism and etiology. Small numbers also constrain epidemio-
logic research and clinical trials as highlighted in Chapters 3 and 5. Other
challenges include the limited funding for research and a limited number of
investigators committed to the study of rare conditions.
The basic research tools available to investigators have advanced dra-
matically over the past 20 years, with new approaches continuing to evolve,
both in the laboratory and from the use of computational biology. Along
with new and better tools, models for supporting discovery research have
also undergone a transformation in recent years. This chapter briefly ex-
amines the implications for rare diseases research of a number of current
research strategies for both target discovery and therapeutic discovery. The
next chapter focuses on product development, particularly from the per-
spective of companies and their academic and government collaborators

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DISCOVERY RESEARCH FOR DEVELOPMENT
BOX 4-1
Examples of Research on Rare Diseases with
Implications for Treatment of Common Conditions
Some of the most effective treatments for coronary artery disease (a very com-
mon condition) were first established during the study of a rare condition called
familial hypercholesterolemia. The disease was ultimately linked to mutations in
the gene for the low-density lipoprotein receptor that coordinates the uptake of
cholesterol from the blood. This work laid the foundation for the development and
use of drugs (specifically, statins) that inhibit the rate-limiting enzyme in choles-
terol synthesis, hydroxymethylglutaryl (HMG)-CoA (coenzyme A) reductase, in the
lowering of circulating cholesterol and the prevention of coronary artery disease
and myocardial infarction (Stossel, 2008).
Patients with a rare condition called osteoporosis-pseudoglioma syndrome have
loss-of-function mutations in the low-density lipoprotein receptor-related protein-5
(LRP5), while mutations causing rare conditions associated with high bone mass
and density produce increased LRP5 function. Subsequent work showed that
LRP5 normally inhibits serotonin production in the gut. Inhibition of gut serotonin
production has emerged as a promising treatment for common causes of os-
teoporosis including the loss of bone mineral density associated with aging and
menopause (Haigh, 2008; Long, 2008).
Aortic aneurysm is the cause of death in about 1 to 2 percent of individuals in
industrialized countries, but its cause is largely unknown and medical treatments
are lacking. During the study of Marfan syndrome, a rare connective tissue
disorder associated with a high risk of ascending aortic aneurysm and tear,
researchers showed that aneurysm development and progression is associated
with increased activity of transforming growth factor β (TGF-β), a molecule that
instructs cellular behavior. It was subsequently shown that interventions that in-
hibit TGF-β, including administration of a neutralizing antibody or the angiotensin
II type 1 receptor blocker losartan, could attenuate or prevent many manifesta-
tions of Marfan syndrome in mouse models. Responsive Marfan phenotypes
included aortic aneurysm, skeletal muscle myopathy, pulmonary emphysema,
and degeneration of the mitral valve. This work prompted the launch of the first
clinical trial for Marfan syndrome based upon a refined understanding of disease
pathogenesis, specifically assessing the efficacy of losartan in attenuating aortic
root growth. Alteration of TGF-β activity was subsequently linked to other rare
(e.g., Loeys-Dietz syndrome) and common (e.g., bicuspid aortic valve with aneu-
rysm) presentations of aortic aneurysm (Jones et al., 2009). Losartan has also
proved effective in the treatment of TGF-β-induced myopathy in a mouse model
of Duchenne muscular dystrophy (Cohn et al., 2007).
who are evaluating and undertaking the complex work needed to transform
promising research discoveries into products that are safe and effective for
patients in need. All along this continuum from basic research through
clinical trials, infrastructure and innovation are needed to accelerate the
development of therapies for people with rare diseases. The discussion here

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focuses on the role of government, industry, academic investigators and in-
stitutions, and advocacy groups. Other groups also contribute, for example,
organizations such as the American College of Medical Genetics.
Both this and the next chapter discuss the infrastructure for rare
diseases research and orphan product development and “innovation plat-
forms” to encourage and support collaborative work. Such collaboration
is needed to bridge the gulf—sometimes referred to as the “valley of
death”—between basic research findings and beneficial products, especially
in the stages that precede clinical studies of efficacy. Early initiatives to
bridge the gulf included public policies such as the Amendments to the
Patent and Trademark Act of 1980 (P.L. 96-517, commonly known as the
Bayh-Dole Act). That legislation encouraged cooperation among academic
institutions, other nonprofit organizations, and small businesses to com-
mercialize research discoveries funded by the federal government (Schact,
2007). Efforts continue to successfully engage government, academic,
nonprofit, and commercial entities as collaborators in translating research
discoveries into safe and effective drugs and medical devices. First, how-
ever, must come the discoveries.
TARGET DISCOVERY
Most rare diseases have a genetic etiology, but the molecular patho-
genesis has been defined for a relatively small number of rare diseases. For
most of this small group, a specific gene alteration is recognized as respon-
sible for the disorder, and for a subset, understanding of the pathogenesis
extends to identification of the function of the affected gene product. For
an even smaller subset, investigators have described targets such as spe-
cific molecules or physiologic pathways that are amenable to therapeutic
modification. The next sections discuss some particular areas of research
advances and their prospects for increasing understanding of the molecular
pathogenesis of rare diseases. Such understanding provides the basis for
modern drug discovery.
Traditional Genetic Studies
Because most rare diseases are caused by defects in a single gene,
identification of a mutated gene is the logical starting point for research in
most cases. Although the standard approach to mapping the chromosomal
location of the gene of interest has used candidate gene analysis or linkage
analysis, these methods are inherently slow and often cumbersome.
Many factors can limit the utility of genetic mapping studies for rare
disorders, notably the lack of large families with multiple affected, surviv-
ing individuals. Early death and other disease-related causes of reduced

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reproduction contribute to this lack as does the general decline in family
size associated with economic and social development. Recent technologi-
cal advances have enabled researchers to employ genome-wide association
studies to identify genetic variation that contributes to the pathogenesis
of common disorders, as well as some of the most prevalent rare diseases
such as juvenile idiopathic arthritis (see, e.g., Thomson et al., 2010). These
studies depend on large patient populations and on an inherent assumption
that the predisposing alleles or haplotypes are both ancient and shared
among unrelated affected patients, effectively precluding this approach for
small patient populations with high locus or allelic heterogeneity. Impaired
reproductive fitness, a feature of many rare disorders, imposes allelic het-
erogeneity and would therefore implicitly disqualify this approach as a
strategy for research on these disorders. Although some critics of genome-
wide association studies argue that they have not been terribly informa-
tive with regard to individual risk of disease, the studies have highlighted
pathways whose relevance to a particular disease had been unsuspected
(Hirschhorn, 2009). Fortunately, additional tools for genetic research are
now available.
Study of Modifier Genes and Epigenetics
Variation in secondary genes can alter primary gene effects and related
pathways and can attenuate or mask underlying disease predisposition.
Studies of these secondary genes are likely to inform the development of
novel therapeutic strategies. For many rare and common disorders, there
is considerable phenotypic variation among individuals with the same un-
derlying primary disease gene mutation. This can be particularly striking
when wide phenotypic variation is seen within individual families. For
example, in X-linked adrenoleukodystrophy (a metabolic disorder that
causes neurological damage), some affected family members have onset
of neurodegeneration and death in childhood, whereas others show mild
manifestations of disease such as isolated adrenal insufficiency that first
manifests in adulthood. Yet other family members may be entirely asymp-
tomatic (Maestri and Beaty, 1992; Moser et al., 2009).
The study of modifier genes can be facilitated through the use of in-
bred mouse strains that often show wide variation in disease severity based
upon the genetic background on which a primary disease-causing muta-
tion occurs. Animal models also offer the ability to use targeted genetic or
pharmacologic perturbations to test focused hypotheses regarding modifier
genes and pathways. The identification of modifier genes is of particular
value in rare diseases, where diagnosis is already difficult due to the small
number of cases.
Beyond germline genetic variation, modification of DNA (e.g., DNA

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methylation, histone acetylation) contributes to rare disorders such as the
Prader-Willi syndrome and Angelman syndrome (Adams, 2008), but it may
be even more important as a contributory factor in modulating gene expres-
sion and, therefore, disease predisposition and severity. These epigenetic
modifications are likely acquired as the result of an array of exposures (e.g.,
prenatal exposure to tobacco smoke) and experiences (e.g., stress). Inves-
tigators are now using microarray and sequencing to analyze methylation
patterns as biomarkers that can have clinical value.
Whole Genome Sequencing, Gene Expression
Analysis, and Exome Sequencing
Whole genome sequencing provides a complete analysis of the en-
tire complement of an individual’s DNA. It can now be used to identify
genetic variants associated with rare diseases in individual patients or
families (Lupski et al., 2010; Roach et al., 2010). The cost for sequencing
has fallen dramatically, but it remains resource intensive and challenging
because each exome contains a large number of polymorphisms (variants),
only one of which is typically the primary gene alteration (Lifton, 2010;
Wade, 2010).
Microarray methods, which are used to comprehensively assess which
genes are transcribed and which are not active in making proteins, are not
diagnostic for genetic diseases. They can, however, be helpful in working out
pathways that are dysfunctional in both genetic and acquired rare disorders
(Wong and Wang, 2008). Experimental methods to interrupt gene expres-
sion in cell culture systems and animal models include the introduction of
target-specific microRNAs, a tool that has been used to confirm the role of
genes and pathways in the pathogenesis and modulation of disease.
Exome sequencing is a promising new approach to the search for
disorder-causing genes for rare diseases (Kuehn, 2010; Tabor and Bamshad,
2010). The method focuses on the less than 5 percent of the genome that
actually codes for protein. With this method, identification of genes associ-
ated with disorders of previously unknown etiology is possible using DNA
from as few as two to four patients (Ng et al., 2009; Johnston et al., 2010).
This approach provides a particular advantage to rare diseases, given that
biological specimens are often scarce. It is expected to accelerate the rate
of identification of gene defects for rare diseases.
Proteomics and Metabolomics
Researchers have made significant progress in the cataloging of genetic
variation and its correlation with disease predisposition, initiation, and
progression. Parallel initiatives for protein variation are also important.

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Proteomics is the science of detecting, identifying, and quantifying the
products of gene translation and represents another approach to uncovering
variation that underlies the pathogenesis of rare diseases. A single gene can
generate an array of protein species based upon alternative translational
start and stop sites and splicing. The derived proteins can be further diver-
sified in relative abundance, structure, and function by posttranslational
modifications including phosphorylation, glycosylation, acetylation, and
tagging for degradation. Proteomics analyses can detect primary pertur-
bations that cause disease (e.g., congenital disorders of glycosylation),
pathogenetic or compensatory pathway activation (e.g., the activation of
kinases through quantitative analysis of substrates for phosphorylation),
and candidate proteins for validation as biomarkers to aid in diagnosis,
prognostication, or therapeutic trials (e.g., newborn screening by tandem
mass spectrometry or detection of increased circulating levels of cardiac
muscle-specific enzymes after myocardial infarction) (see, e.g., Duncan and
Hunsucker, 2005; Haffner and Maher, 2006; Suzuki et al., 2009; Van Eyk,
2010). One challenge is that proteomic analysis requires expensive equip-
ment (e.g., mass spectrometry) and data analysis tools, which means that
this technique is usually centralized in special laboratories.
Metabolomics involves the study of the small-molecule metabolites
found in an organism. As in proteomics, mass spectrometry can be used
As
to detect abnormal metabolic products, to diagnose rare diseases, and to
understand alterations in relevant biological pathways. An example is the
elucidation of a series of synthetic enzyme deficiencies that result in the
production of abnormal bile acids leading to serious liver, neurologic, con-
nective tissue, and nutritional disorders (Heubi et al., 2007).
Systems Biology and Bioinformatics
With the aid of translational bioinformatics (Schadt et al., 2005a;
Vodovotz et al., 2008), the construction of molecular networks and path-
ways relevant to specific rare disorders is increasingly possible. Bioinfor-
matic analyses of data from gene expression arrays, proteomics studies, and
clinical observations on patients with rare diseases can define signatures of
fundamental disease mechanisms (Dudley et al., 2009; Patel et al., 2010;
Suthram et al., 2010). Integration of this information with signatures of
drug activities or therapeutic responses could intuitively promote discovery
regarding the etiology, pathogenesis, and treatment of unclassified or poorly
understood disorders (Schadt et al., 2005b). For example, if two diseases
show overlapping or identical signatures, established treatments for one
might benefit the other. Drugs that show signatures that oppose those seen
for certain diseases emerge as candidate therapies. Bioinformatic methods
can screen known chemical compounds for structural characteristics that

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predict desired drug activities that are potentially beneficial for patients
with rare diseases. Identification of drugs with overlapping signatures will
promote the informed testing and substitution of agents that might show
greater efficacy or other desirable characteristics such as reduced toxicity.
Through these approaches, it should be possible to identify multiple inter-
vention target sites for some disorders.
Conversely, studies of biological networks can also identify common
pathways for multiple rare diseases that are biologically related. For ex-
ample, a more comprehensive understanding of the molecular basis for
lysosomal function may provide an opportunity for interventions that are
beneficial for an array of lysosomal disorders (Sardiello et al., 2009). More
broadly, this capability may open the door for the discovery of single
therapies that can benefit multiple rare disorders and, potentially, also more
common diseases.
The promise of systems biology is built on the availability of molecular
and genetic data, combined with the development of valid computational
methods for integrating these data into predictive models of disease (Schadt,
2005a). Although most genomic sequences are available in publicly acces-
sible databases, many experimental biological data as well as clinical trials
data are not collected or stored in a way that ensures broad access to the
information. Thus, as discussed later in this chapter, the infrastructure for
rare diseases research and product development should include structures
and processes for sharing research resources, including data and biological
specimens.
THERAPEUTICS DISCOVERY
Once basic research is performed and findings implicate a specific
biological target, which could be an enzyme, a product of a biochemical
pathway, an altered gene, an epigenetic mechanism, or a combination of
the above, then the search begins for an appropriate therapeutic agent.
Sometimes recognition of a molecular defect can point directly to potential
therapies.
Effective therapies can either inhibit deleterious or excessive functions
or restore missing functions, both of which can result from gene mutations.
In the former category, for example, the finding that transforming growth
factor β (TGF-β) plays a role in the development of aortic root aneurysms
in Marfan syndrome led to studies of an inhibitor of TGF-β (angiotensin
II type I receptor inhibitor losartan) that are currently in phase III trials
(Dietz, 2010). A large number of monoclonal antibodies are available to
modulate exuberant immunologic, inflammatory reactions in rare as well
as more common diseases. Imatinib successfully treats CML and other
cancers by inhibiting tyrosine kinases. Increasingly, small interfering RNAs

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(siRNAs) are being tested as inhibitory drugs, systemically and by direct
instillation into the central nervous system and other tissues (Dykxhoorn
and Lieberman, 2006).
A few disorders can be treated with “curative” therapies that restore
missing functions. Examples of such conditions and treatments include
congenital hypothyroidism (replacement of thyroid hormone), bile acid
synthetic enzyme deficiencies (oral bile acid therapy), biotinidase deficiency
(biotin vitamin therapy), and celiac disease (dietary avoidance therapy).
Still, for most rare diseases an obvious and easy therapeutic remedy is elu-
sive or beyond current scientific capabilities. As discussed in Chapter 2, for
most rare conditions, treatment is limited to symptomatic therapies (see,
e.g., Campeau et al., 2008; Dietz, 2010).
High-Throughput Screening of Compound Libraries
When a potentially relevant target for an identified disease is validated,
chemists then mount an intensive search for chemicals that might modify
the target or targets. They screen vast compound libraries that are primar-
ily assembled and secured within pharmaceutical companies to develop a
list of potential “hits” that might some day become a “lead compound”
and eventually new medicine, almost always after extensive “medicinal”
chemistry to improve various properties of the parent compound and turn
it into a drug suitable for testing in humans. This sophisticated process
can be divided into three distinct steps: (1) development and maintenance
of large compound libraries, (2) specific assay development, and (3) high-
throughput screening.
Assays are analyses that quantify the interaction of the biological target
and the compound that the researchers are investigating. They also might
measure how the presence of the compound changes the way in which the
biological target behaves. The chemical compounds tested in these assays
are maintained in large compound libraries, which may contain more than
5 million chemicals. Products from natural sources such as plants, fungi,
bacteria, and sea organisms can be integrated within compound libraries.
Most compounds, though, are derived through the use of chemical synthesis
techniques, in which researchers create chemical compounds by manipu-
lating “parent” chemicals. They might also use combinatorial chemistry,
in which researchers create new but related chemical compounds and test
them rapidly for desirable properties. Sometimes companies will provide
compounds to laboratories for low-volume screening, or alternatively the
assay for the molecular target can be provided to a company where it will
be optimized for high-throughput screening.
Testing the expanding number of available biological targets against
thousands or millions of chemical entities requires highly sophisticated

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screening methods. Researchers use robotics, for example, to simultane-
ously test thousands of distinct chemical compounds in functional and
binding assays. Academic researchers with expert knowledge of specific
pathways may guide the development of assays in collaboration with indus-
try. The chemical compounds identified through this kind of screening can
provide powerful research tools that contribute to a better understanding
of biological processes. This, in turn, may lead to new targets for potential
drug discoveries.
The purpose of this chemistry stage is to refine the compound. Hun-
dreds and possibly thousands of related compounds may be tested to
determine if they have greater effectiveness, reduced toxicity, or improved
pharmacological behavior, such as better absorption after a patient takes
the drug orally.
To optimize the molecules being investigated, scientists use computers
to model the structure of the lead compounds and how they link to the
target protein—an approach to structure-based design known as in silico
modeling (silico referring to the silicon technology that powers comput-
ers). This kind of structural information gives chemists a chance to modify
lead molecules or compounds in a more rational way. This refinement
process is called lead optimization, which may produce a drug candidate
that has promising biological and chemical properties for the treatment of
a disease.
Once a candidate drug (or group of candidates) is developed and its
effectiveness in altering the molecular target is verified, then animal stud-
ies begin to determine whether the drug can be absorbed through the
gastrointestinal tract for oral delivery, whether adequate levels of the drug
are achieved in the blood, how the drug is metabolized in the body and
excreted, and whether it actually reaches the molecular target defined by
the basic research. In addition, if an animal model of the rare disease exists
(through genetic alterations), this provides researchers with an opportunity
to gather a preclinical proof of therapeutic concept, which can be very im-
portant before the compound enters development. This process of drug dis-
covery for rare diseases is no different than that for common diseases—the
costs and infrastructure required for both are significant.
Methodological Approaches to Biologics Discovery
For a biologic product (e.g., a specific protein, enzyme, peptide, anti-
body, or vaccine), the discovery phase varies considerably from the process
for a small-molecule drug described above. It requires different areas of
expertise, some of which can be found at academic institutions and others
of which are available at biotechnology and pharmaceutical companies.

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If the defect in a specific rare disease is due to deficiency of a specific
protein, then human protein replacement therapy may be a feasible ap-
proach. To accomplish this, the replacement protein can either be isolated
from other animals or, more commonly, be expressed in microorganisms or
plant, nonhuman mammalian, or human cells after introduction of a gene
encoding the desired human protein (so-called recombinant expression).
This process can be extremely complicated. Some proteins require specific
modifications (called posttranslational modifications) that are only accom-
plished by specific organisms or cell types. Other proteins require artificial
modifications to target them to a specific tissue or cell type or to facilitate
their uptake into cells, if that is where their critical function resides. For
example, for some lysosomal enzyme deficiency diseases, it is critical to tar-
get the replacement protein for uptake in liver or muscle cells, whereas for
other diseases, the replacement protein must have different modifications
that promote uptake by reticuloendothelial cells (Grabowski and Hopkin.
2003). Not all obstacles have found solutions. Currently, a sizable number
of rare diseases that affect the brain present a major challenge since many
biologics lack the ability to cross from the circulation into the central
nervous system (the so-called blood-brain barrier). Researchers continue
to investigate strategies for overcoming this problem (see, e.g., LeBowitz,
2005; Valeo, 2010).
Given this complexity, there is no single path to success for biologic
therapeutics. Rather, the opportunities and obstacles must be elucidated
for each disease, and the approach must be tailored accordingly—a truly
daunting task for thousands of rare disorders. Nevertheless, biologics have
strong appeal because they have the potential to address the etiologic
foundation of a disease process (e.g., through replacement of a deficient
protein), to prevent diseases (e.g., with vaccines), or to harness the power
of the immune system to achieve target specificity and to diversify the out-
put of potential therapeutic agents (e.g., by production of an antibody that
neutralizes a deleterious protein). Good examples include clotting factor
proteins to treat hemophilia, vaccines to prevent smallpox or measles, and
antibodies to treat multiple forms of cancer (Reichert et al., 2005).
Restoration of functional levels of missing molecules includes enzyme
replacement therapy, available for several lysosomal storage diseases. Among
these are Gaucher disease, Fabry disease, mucopolysaccharidosis I and VI,
and Pompe disease (Lim-Melia and Kronn, 2009). Enzyme therapy is also
employed for one form of severe combined immunodeficiency, adenosine
deaminase deficiency (Aiuti et al., 2009). These approaches have required
research efforts to express the protein yeast, bacteria, plant, or mamma-
lian cell systems at small laboratory scale to provide sufficient enzyme for
research studies. Enzyme therapy does not correct central nervous system

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by an NIH Clinical and Translational Science Award) and seeks to create
opportunities for medical and graduate students to build and execute a
product development plan for new chemical entities and other discoveries
generated by Stanford faculty that are not far enough advanced to attract
industry interest. The program provides faculty and industry-experienced
mentors for competitively selected projects. One emphasis is product de-
velopment targeted to rare and neglected diseases, including through the
repurposing of old drugs or the reconsideration of abandoned ideas or proj-
ects. Several products have been licensed and are in clinical development,
which suggests that the goals of this program—education, stimulation of
applied research, and commercialization of intellectual property—are being
achieved. This is one example of an innovation platform that could acceler-
ate future orphan products development.
Among particular needs for clinical-translational investigators in rare
diseases is training in trial designs that can be applied to studies of small
populations of patients with rare diseases. These investigators will also have
to recognize when they need consultants to give them more expert guid-
ance. Clinical subspecialists who work with both children and adults with
rare diseases should be trained to collect data that will lead to standardized
and detailed phenotyping and the elucidation of clinical natural histories,
two potentially important contributions to research progress related to rare
diseases. Training in systems biology and bioinformatics will also be key for
future investigators working in rare diseases areas because these disciplines
hold the potential to rapidly advance knowledge and its application to rare
diseases. Beyond scientific training, successful investigators must know how
to build and sustain productive collaborations and must be comfortable
communicating their work to interdisciplinary audiences.
Training of young investigators or retraining of experienced inves-
tigators to conduct research on specific rare diseases will depend on the
existence of productive and funded programs in rare disorders-specific
research that can serve as training sites for both basic and clinical research.
Thus, adequate funding for rare diseases research is an important first step
in establishing training environments. Funding from NIH, other federal
agencies, and disease-specific advocacy groups serves the dual purpose of
fostering research progress and exposing investigators-in-training or young
investigators to the relevant research activities.
The federal government through NIH and other agencies provides
training grants, which may focus on individuals or programs (an example of
the latter is the T-32 grants from NIH). These grants target specialty fellows
in relevant medical subspecialties and graduate students or postdoctoral
graduate fellows. Some disease-specific foundations also support training
and young investigator grants.

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Targeted career development awards for young faculty are particularly
important in promoting and sustaining interest in and activity related to
rare diseases. Examples of such awards include the K series grants from
NIH and young investigator grants from CFF (e.g., the Leroy Matthews
and Harry Shwachman Awards). The Dana Foundation’s competitive grants
programs in brain and immunoimaging and neuroimmunology primarily
support new investigators with innovative clinical research hypotheses to
develop pilot data on brain or spinal cord diseases, most of which are rare.
Some of these new investigators have NIH K-08 (or K-23) mentored grants,
which provide up to 75 percent of their salaries, and Dana funds support
the remaining 25 percent. Both Dana and the NIH training grants support
the new investigators’ salaries, and other research-related costs often are
supported by the investigators’ institutions. The Burroughs Wellcome Fund
offers a postdoctoral fellow-to-faculty transition grant for physician scien-
tists, a model for the NIH K99-R00 awards. This approach is particularly
effective at establishing early independence for fellows (Pion and Ionescu,
2003), and it could be employed more broadly for researchers in rare dis-
eases areas.
The committee did not locate any compilation of resources for training
related to rare diseases. Thus, it was difficult to judge the current amount
of training or its content as a basis for identifying specific gaps. The em-
phasis here is therefore more generally on the need for training in basic
and translational or clinical research areas that will be relevant to many
rare diseases.
INNOVATION PLATFORMS FOR TARGET AND DRUG DISCOVERY
The high costs and low success rates associated with drug discovery and
development, combined with the absence, in the case of rare diseases, of a
large market for approved therapies, have stimulated the development of
innovation platforms on a number of levels. One typical characteristic of
these emerging approaches involves the sharing of the data, biological speci-
mens, chemical compounds, and other resources that are needed at various
stages to move from discovery to product approval and marketing.
Another characteristic is the involvement of funding organizations
beyond their traditional roles of supporting research projects and train-
ing. Some patient-led foundations have taken on the task of “de-risking”
the early stages of drug discovery through early-stage clinical trials, for
example, by combining an infusion of philanthropic capital with the de-
velopment of research tools and organized access to patients. For example,
CFF has assembled drug discovery tools of potential interest to the scien-
tific community working on the disease: an antibody distribution program,

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primary human epithelial cells harvested from lung transplants, a purified
CFTR (cystic fibrosis transmembrane conductance regulator) protein sup-
ply, and validated assay services. These efforts of CFF and others are sum-
marized in Chapter 5. NIH has also created new internal capacities and new
partnership mechanisms for facilitating drug discovery, which are described
in this section.
Public-Private Partnerships and Other Coordinating Strategies
Public-private partnerships have been a standard approach when the
needs of the public sector converge with goals of the private sector, prompt-
ing the joint provision and management of resources for targeted projects.
Examples include the delivery of services or facilities in the energy, trans-
portation, education, or urban development sectors. NIH defines a public-
private partnership as an agreement for the agency “to work in concert
with a nonfederal party or parties to advance mutual interests to improve
health” (NIH, 2007, p. 2). Although gifts, clinical research contracts and
other contracts, and technology transfer agreements involve relationships
with a nonfederal party or parties, NIH does not consider these arrange-
ments to be partnerships. Other groups may have more expansive interpre-
tations of the concept.
The formation of public-private partnerships involving government,
industry, and nonprofit organizations has been a successful model for the
infrastructure gaps in the area of neglected tropical diseases, which share
with rare diseases the lack of commercial incentives for product devel-
opment. For example, the multilateral Special Programme for Research
and Training in Tropical Diseases (Morel, 2000; Ridley, 2003) and, more
recently, the Medicines for Malaria Venture (Ridley, 2002) combine gov-
ernment, philanthropic, and industry funding2 and enlist the expertise of
an external scientific advisory board to select projects for support. These
initiatives coordinate activities between industry and academic centers (e.g.,
sharing of compound libraries) to discover new molecules for the treat-
ment of tropical diseases and shepherd them through the subsequent stages
along the discovery-development pipeline, thereby acting as “virtual bio-
tech” companies. Projects not meeting specified milestones are dropped
and replaced with others, such that each organization manages a portfolio
2 The malaria venture was, for example, initially cosponsored by the World Health Organi-
zation, the International Federation of Pharmaceutical Manufacturers Associations (IFPMA),
the World Bank, the Dutch government, the Department for International Development in the
United Kingdom, the Swiss Agency for Development and Cooperation, the Global Forum for
Health Research, the Rockefeller Foundation, and the Roll Back Malaria Partnership.

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of projects with varying degrees of risk (MMV, 2002, 2003; Nwaka and
Ridley, 2003; TDR, 2008).
An example of a public-private partnership in the rare diseases area is
the Spinal Muscular Atrophy project (http://www.smaproject.org/). Estab-
lished by the National Institute of Neurological Diseases and Stroke, the
pilot project is a multisite drug discovery and development enterprise that
is guided by consultants with academic, FDA, NIH, and pharmaceutical
industry expertise. The project focuses on optimizing lead compounds and
making them available to researchers for preclinical testing.
NIH has initiated several broader programs to support drug discovery
for rare diseases. The NIH Chemical Genomics Center (NCGC), which was
established as part of the NIH Roadmap, focuses on novel targets as well
as roughly a dozen rare and neglected diseases. As described on its web-
site, it will “optimize biochemical, cellular and model organism-based as-
says submitted by the biomedical research community; perform automated
high-throughput screening (HTS); and perform chemistry optimization on
confirmed hits to produce chemical probes for dissemination to the research
community” (http://www.ncgc.nih.gov/about/mission.html). The NCGC is
also building a library of approved drugs so that these compounds can be
more easily screened for possible repurposing for new indications; it has
undertaken screening related to certain lysosomal storage diseases among
other rare conditions (Austin, 2010).
The Therapeutics for Rare and Neglected Diseases (TRND) program,
which was established in 2009, will collaborate with the NCGC as well
as companies and nonprofit patient groups; it thus can be considered
a public-private partnership (NIH, 2009b). The program aims to bring
promising compounds to the point of clinical testing and adoption for
further development by commercial interests. TRND, which had an initial
budget of $24 million a year, is expected to ramp up to work on roughly
five projects per year. Its first pilot projects involve sickle cell disease,
chronic lymphocytic leukemia, Niemann-Pick Type C, hereditary inclusion
body myopathy, and the parasitic diseases schistosomiasis and hookworm
(Marcus, 2010b). (The NIH Rapid Access to Interventional Development
program, which takes projects through preclinical development, is dis-
cussed in Chapter 5.)
TRND is a much-needed and innovative development. However, its
scope (five projects per year) is well below the number of rare diseases that
need therapies and have researchers positioned to take advantage of this
capability. In addition, extension of services to include access to animal
models of rare diseases could facilitate preclinical studies, a frequent barrier
to therapeutic development. Expansion of both capacity and geographical
distribution of TRND activities could advance therapeutics development
for more rare diseases.

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Sharing Biological Data on Disease Mechanisms
As discussed earlier in this chapter, arriving at a candidate drug requires
extensive basic research into the disease mechanism, identification of poten-
tial targets for the drug, and generation of extensive molecular and genetic
data. Typically, these mechanistic data are held by intrinsically competitive
academic or industry labs that may have interests in protecting publication
priorities or intellectual property or both. One consequence is that the data
are not collected or stored in a way that ensures broad access to the infor-
mation. This, in turn, has slowed the pace of information dissemination and
driven up the cost of drug discovery.
In recent years, several developments have challenged this approach,
particularly in the pharmaceutical industry. One development is the growing
recognition that many research questions in human diseases are too complex
for any one laboratory or any one company (Duncan, 2009). Another de-
velopment is accumulating research that shows that many common diseases
actually consist of subsets of disease based on their molecular characteristics,
which often determine how individuals will respond to therapy. As a result,
what might once have been a potentially large market of patients for a par-
ticular therapy is fragmented into a number of small markets. At the same
time, companies have seen increasing costs of drug discovery and develop-
ment without a corresponding increase in productivity of the industry, as
measured by output of new molecular entities (Munos, 2009).
Taken together, these trends are stimulating innovation in the form of
initiatives to share data “precompetitively” (see, e.g., Stoffels, 2009; Hunter
and Stephens, 2010; Marcus, 2010a; but see also Munos, 2010). A recent
workshop at the Institute of Medicine explored the opportunities and chal-
lenges of such collaborations, some of which involve only private entities
(e.g., several companies or advocacy groups and companies) whereas others
also involve the public sector (IOM, 2010b).
One model of precompetitive collaboration outside the health care
arena is the development of the Linux operating system, which involved
competitors sharing the benefits of increased productivity resulting from
joint, voluntary investments in early-stage research. Given the increasing
information richness of biology, similar integration of knowledge about
biochemical pathways and networks from a wide range of researchers may
spur productivity in the identification of molecular targets for diseases and
otherwise advancing discovery research and product development. Exist-
ing examples of such efforts to share biological information or technology
development resources include the following:
• Enlight Biosciences, a private company created in partnership with
major pharmaceutical companies to develop enabling technologies that

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will alter the process of drug discovery and development (Zielinska, 2009);
and
• voluntary, open-source sharing of biological data through the Sage
Commons, an initiative of Sage Bionetworks, a new, nonprofit medical
research organization (http://sagebase.org).
The second example, Sage Bionetworks, uses data shared by phar-
maceutical companies and others to develop computational models that
predict potential drug targets as well as potential toxicities (Melese et al.,
2009). The data shared with Sage will eventually be publicly available and
could be particularly valuable for rare diseases research. For example, the
organization has already provided a significant amount of clinical data to
the Huntington disease research community. The data were generated in a
clinical study of Alzheimer disease in which individuals with Huntington
disease were used as controls. Without the Sage resource, these data would
likely have remained unknown and unavailable to Huntington disease in-
vestigations (Marcus, 2010a).
Some rare diseases advocacy groups have made the sharing of re-
search data by grant recipients a prerequisite for funding. For example,
through its Accelerated Research Collaboration model, the Myelin Re-
pair Foundation has insisted that those funded in its collaborations share
their research findings with one another without awaiting scientific pub-
lication (MRF, 2010). To cite another example, in 2007 the Multiple
Myeloma Research Consortium launched a Genomics Portal, through
which researchers have unrestricted access to prepublication genomic and
other molecular data (Kelley, 2009). This approach is not conventional
in academic environments where researchers are rewarded for individual
achievement, but by mandating data sharing, the consortium has succeeded
in significantly expanding the therapies currently under development for
multiple myeloma.
Sharing Compound Libraries
A related trend is the opening of what were once proprietary company
libraries of chemical compounds to investigators interested in the potential
of compounds to interact with drug targets across a wide range of diseases.
Compounds and information on their structures have typically been gener-
ated and held tightly by pharmaceutical companies. In recent years, com-
panies have begun sharing compound libraries with researchers working in
neglected diseases areas. For example,
• Eli Lilly Co. is sharing its compound libraries with researchers
seeking therapies for tuberculosis (http://www.tbdrugdiscovery.org/);

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• Pfizer Inc. has signed an agreement with the Drugs for Neglected
Diseases initiative to share its library of novel chemical entities so that
investigators can screen it for potential treatments for human African
trypanosomiasis, visceral leishmaniasis, and Chagas disease (DNDi, 2009);
and
• GlaxoSmithKline will share the chemical structures of compounds
with potential activity against malaria through websites supported by fed-
eral, for-profit, and foundation funding (Guth, 2010).
In addition to the compound sharing initiative noted above, Eli Lilly
has also established the Phenotypic Drug Discovery Initiative (https://pd2.
lilly.com/pd2Web/). The company provides access to a phenotypic assay
panel at no cost to external investigators, who can make a confidential
compound submission and receive a full data report in return. Promising
findings can lead to a collaboration agreement.
In the area of neglected diseases, access to compound libraries and
chemical structures can significantly lower the threshold for pursuing drug
discovery and development. Similarly, the European Rare Diseases Thera-
peutic Initiative has worked to bring about such access for academic institu-
tions pursuing treatments for rare diseases (Fischer et al., 2005). To address
intellectual property concerns, it has been proposed that compounds with
commercial value might be accessed using a trusted intermediary, with
initial confidentiality about the compound maintained and companies’
reserving the option of first refusal for development (Rai et al., 2008). The
experience with these efforts might inform the development of institutional
mechanisms to facilitate access to proprietary compound libraries.
RECOMMENDATIONS
Two critical issues for rare diseases research are the small number
of patients available to participate in research on rare diseases and the
limited sources of funding for discovery and development of potential
therapies for these diseases. It is therefore particularly important to make
the best use possible of the information and other products that research
generates—whether the research is directed specifically at a rare condition
or at a more common condition that potentially has relevance for a rare
condition. Making the best use of information and resources has several
dimensions that target problems created by current practices. These prob-
lems include
• institutional and individual interests—economic, reputational, and
professional—that can impede collaboration and resource sharing even as
they may also stimulate innovation;

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• fragmented, proprietary patient registries that have developed in
the absence of consistent standards for the creation of accurate, usable
information;
• fragmented, poorly preserved, and inaccessible biospecimen collec-
tions; and
• other resources such as biological data and research findings that
are not broadly accessible to researchers who may then have to collect that
information anew.
The committee does not underestimate the diverse barriers to resource
sharing and collaboration or the need for creativity and patience in dealing
with them. Nonetheless, it believes that the initiatives cited above illustrate
promising strategies for either overcoming or coexisting with these barriers.
As components of an integrated policy to accelerate rare diseases re-
search, several steps can be taken to develop a system that will support
the sharing of resources, for example, compound libraries, and discourage
the creation of a duplicative infrastructure. In some instances, steps may
include the required sharing of research resources, for example, tissue speci-
mens and data generated by federally funded or foundation-funded research
on rare diseases. What is envisioned is essentially a “research commons”
and public-private partnership (or series of partnerships) that has several
unlinked or loosely linked elements.
RECOMMENDATION 4-1: NIH should initiate a collaborative effort
involving government, industry, academia, and voluntary organizations
to develop a comprehensive system of shared resources for discovery
research on rare diseases and to facilitate communication and coopera-
tion for such research.
Creating such a system of shared resources for rare diseases research
will require a significant developmental effort and commitment of public,
commercial, and nonprofit funding and other resources, for example, as-
sistance in creating mechanisms for coordination and oversight and model
provisions for public access to the information developed with government
and nonprofit grant support. Key elements of this system would include,
among other possible features,
• a repository of publicly available animal models for rare disor-
ders that reflect the disease mechanisms and phenotypic diversity seen in
humans;
• a publicly accessible database that includes mechanistic biological
data on rare diseases generated by investigators funded by NIH, private
foundations, and industry;

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• common platforms for patient registries and biorepositories (see
Chapter 5);
• model arrangements and agreements (e.g., template language on
intellectual property) for making relevant portions of compound libraries
available to researchers in rare diseases areas; and
• further exploration of precompetitive models and opportunities
for developing technologies and tools for discovery research involving rare
diseases.
Given the challenges outlined in this chapter and other parts of this
report and given the important role that NIH plays in supporting research
on rare diseases, the committee believes that a comprehensive NIH action
plan on rare diseases would be useful to better integrate and expand exist-
ing work. This plan would take into account developments since the 2000
report of a special panel on coordinating rare diseases research programs
within NIH (NIH, 2000). The following recommendation spans all phases
of research on rare diseases and orphan products. Thus, it supports not
only the discovery research discussed in this chapter but also the product
development work and recommendations discussed in Chapter 5. It would
likewise encompass research and development involving medical devices for
people with rare diseases.
RECOMMENDATION 4-2: NIH should develop a comprehensive ac-
tion plan for rare diseases research that covers all institutes and centers
and that also defines and integrates goals and strategies across units.
This plan should cover research program planning, grant review, train-
ing, and coordination of all phases of research on rare diseases.
The development of an action plan would, at various points, necessarily
involve consultation with FDA, advocacy groups, and industry. It likewise
would involve consultation with investigators and academic institutions
engaged in rare diseases research and product development.
The aspects of the plan that involve training would include incentives
to attract new and established academic investigators to the study of rare
diseases and orphan products and also support investigators currently
studying rare diseases. Such a plan could include a loan repayment program
for investigators working on rare diseases, the creation of an award for
highly innovative proposals for rare diseases, and the broader use of the
K99-R00 (Pathway to Independence) awards to attract outstanding new
investigators in rare diseases research. Training opportunities through the
NIH intramural research programs could also be identified. In addition, the
program could include a mechanism for identifying training opportunities
(especially in computational science, small clinical trial design, and orphan

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products development) that are particularly useful for investigators of rare
diseases. Likewise, the program could support the identification, develop-
ment, and replication of successful training models for investigators in rare
diseases.
For all investigators, the creation of an award similar to the NIH
Director’s Pioneer Awards could provide an incentive and a reward for in-
novation. It would also draw attention to the opportunities for rare diseases
research. These awards are intended to support investigators of outstanding
creativity who propose truly innovative and even transforming biomedical
research.
With respect to the review of proposals for research on rare diseases,
the NIH action plan would include the development of guidance for study
sections and institute councils. This guidance would, for example, clarify
the potential public health relevance of rare diseases research, the range of
appropriate methods for studying rare diseases, and the use of alternative
mechanisms to ensure expert review of grant applications on rare diseases.
Such mechanisms could include appointing special experts on rare dis-
eases as primary reviewers to existing study sections, including rare dis-
eases experts in the Center for Scientific Review, or creating a study section
dedicated to rare diseases grants. More generally, NIH could investigate
means of accelerating its decisions about preclinical (and clinical) awards
for research on rare diseases.
Further, as discussed in Chapter 3, NIH and FDA should continue to
cooperate in developing training and guidance to improve the quality of
NIH-funded rare diseases and orphan products research and increase the
likelihood that the research—including preclinical studies—will provide ac-
ceptable evidence for FDA review of marketing applications for drugs and
biologics. For example, one element of the action plan could be a focused
Request for Applications for natural history studies of rare diseases to help
identify therapeutic targets for rare diseases or build the evidence base to
support FDA approval of a specific drug being studied with NIH support.
The lack of natural history studies has been identified as a problem in Chap-
ter 3. Such studies are one focus of the Rare Diseases Clinical Research
Network, but this network (as described in Chapter 5 and Appendix E)
supports only 19 consortia that study approximately 165 rare conditions.
NIH also funds a number of studies outside the network, but the natural
history of many more rare diseases remains to be studied.
Another element of the action plan would be the development of a
systematic, reliable, and comprehensive system for identifying and track-
ing public and private funding for rare diseases studies to help highlight
gaps and opportunities for public and private research sponsors. As more
private foundations and research initiatives are created, the lack of inte-
grated information on funding will become a more serious problem and

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will interfere with the ability of these groups to target their resources and
collaborate effectively.
The following chapter shifts the focus from basic research to the pre-
clinical and clinical development investigations that are required to establish
safety and efficacy and otherwise meet regulatory standards for approval of
pharmaceuticals and biologics. It concludes with additional recommenda-
tions for resource sharing and collaboration.